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Normal Human Pituitary Gland and Pituitary Adenomas Express Cannabinoid Receptor Type 1 and Synthesize Endogenous Cannabinoids: First Evidence for a Direct Role of Cannabinoids on Hormone Modulation at the Human Pituitary Level¹

Neuroendocrinology Group (U.P., M.T., Y.G., J.S., T.A., G.K.S.) and Molecular Genetics of Behavior Group (G.M., B.L.), Max Planck Institute of Psychiatry, 80804 Munich, Germany; Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico, Consiglio Nazionale delle Ricerche (F.F., A.M., V.D.M.), 80072 Arco Felice, Naples, Italy; and Neurosurgical Department, Hospital San Raffaele (M.L.), 20132 Milan, Italy

Address all correspondence and requests for reprints to: Dr. Uberto Pagotto, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804 Munich, Germany. E-mail: pagotto{at}mpipsykl.mpg.de

Abstract

Little is known about the expression and function of cannabinoid receptor type 1 (CB1) in the human pituitary gland. The aim of this study was to investigate CB1 expression in human normal and tumoral pituitaries by in situ hybridization and immunohistochemistry using an antibody against CB1. CB1 was found in corticotrophs, mammotrophs, somatotrophs, and folliculostellate cells in the anterior lobe of normal pituitary. After examination of 42 pituitary adenomas, CB1 was detected in acromegaly-associated pituitary adenomas, Cushing’s adenomas, and prolactinomas, whereas faint or no expression was found in nonfunctioning pituitary adenomas. Experiments with cultured pituitary adenoma cells showed that the CB1 agonist WIN 55,212–2 inhibited GH secretion in most of acromegaly-associated pituitary adenomas tested and that the CB1 antagonist SR 141716A was generally able to reverse this effect. Moreover, WIN 55,212–2 was able to suppress GHRH-stimulated GH release, and this effect was not blocked by coincubation with SR 141716A, possibly indicating a non-CB1-mediated effect. In contrast, WIN 55,212–2 was ineffective on GH-releasing peptide-stimulated GH release. In four Cushing’s adenomas tested, WIN 55,212–2 was not able to modify basal ACTH secretion. However, simultaneous application of CRF and WIN 55,212–2 resulted in a synergistic effect on ACTH secretion, and this effect could be abolished by SR 141716A, demonstrating a CB1-mediated effect. In the single case of prolactinomas tested, WIN 55,212–2 was able to inhibit basal secretion of PRL. Finally, the presence of endocannabinoids (anandamide and 2-arachidonoylglycerol) was investigated in normal and tumoral pituitaries. All tumoral samples had higher contents of anandamide and 2-arachidonoylglycerol compared with the normal hypophysis. Moreover, endocannabinoid content in the different pituitary adenomas correlated with the presence of CB1, being elevated in the tumoral samples positive for CB1 and lower in the samples in which no or low levels of CB1 were found. The results of this study point to a direct role of cannabinoids in the regulation of human pituitary hormone secretion.

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